Role of ion exchangers in mediating NaCl transport in the proximal tubule

The reabsorption of NaCl in the proximal tubule occurs passively through the paracellular pathway, and actively by a transcellular route. Transcellular NaCl transport involves Na+-coupled Cl- entry across the apical membrane by two mechanisms involving Cl--organic anion exchange. One mechanism is Cl--formate exchange with recycling of formate from lumen to cell by H+-coupled formate transport in parallel with Na+-H+ exchange. A second mechanism is Cl--oxalate exchange with recycling of oxalate from lumen to cell by oxalate-sulfate exchange in parallel with Na+-sulfate cotransport. Cl- exit across the basolateral membrane is most likely mediated by Cl- channels. Apical membrane Na+-H+ exchange is involved in mediating both NaHCO3 and NaCl reabsorption in the proximal tubule. Immunocytochemical studies indicate that NHE3 is the principal Na+-H+ exchanger isoform expressed on the brush border membrane. Detection of NHE3 in a subapical, intracellular, vesicular compartment in proximal tubule cells is consistent with its possible regulation by membrane trafficking. That NHE3 is the isoform responsible for apical membrane Na+-H+ exchange activity is supported by studies of inhibitor sensitivity, and by studies demonstrating increased expression of NHE3 protein in association with enhanced Na+-H+ exchange activity during renal maturation and in response to glucocorticoids and metabolic acidosis.